The present invention relates to a method for producing a pyridine compound that is useful for photographic additives, sensitizing dyes, pharmaceuticals, organic EL materials, liquid crystal materials, nonlinear optical materials, and so on, or for synthetic intermediates of these materials.
Examples of methods for synthesizing pyridine compounds by oxidation of a dihydropyridine compound include an oxidation method using oxygen (as described, for example, in Bull. Chem. Soc. Jpn., 57(7), 1994-1999 (1984); Tetrahedron Lett., 23 (4), 429-432 (1982); and Synth. Commun., 21 (3), 401-406 (1991)); an oxidation method using sulfur (as described, for example, in Chem. Pharm. Bull., 38 (1), 45-48 (1990); J. Org. Chem., 53 (18), 4223-4227 (1988); and JP-A-6-172347 (xe2x80x9cJP-Axe2x80x9d means unexamined published Japanese patent application)); an oxidation method using o-chloranil (as described, for example, in J. Org. Chem., 48 (24), 4597-4605 (1983); and Heterocycles, 22 (2), 339-344 (1984); and an oxidation method using DDQ (as described, for example, in Tetrahedron, 48 (27), 5647-5656 (1992); and Heterocycles, 45 (3), 434-438 (1997)). However, these methods had disadvantages that the reaction required a long time or high temperature, and moreover, post-treatment, such as removal of a residue, also required much time. Accordingly, it is difficult to say that these methods were suitable for industrial production. Further, these methods were also unsatisfactory as industrial production methods from the viewpoints of cost and environment.
Further, purification techniques, such as chromatography and distillation, have been employed to yield a pyridine compound of high purity. However, the chromatography requires so much chromato-carrier and elution solvent that it is not suitable for industrial production. The distillation also has the problem that it is difficult to purify a pyridine compound having a low melting point or a high boiling point.
The present invention is a method for producing a pyridine compound represented by formula (II), which comprises oxidizing a dihydropyridine compound represented by formula (I), in the presence of (i) at least one acid and at least one compound selected from the group consisting of nitrous acid and a nitrite, or (ii) at least one base and a hydrogen peroxide solution: 
wherein each of R1 to R5 independently represents a hydrogen atom, or a substituent; L represents an alkyl group, an alkoxy group, an aryl group, or an aryloxy group, each of which may have a substituent: 
wherein each of R1 to R5 has the same meanings as those of formula (I).
Further, the present invention is a method for producing the pyridine compound represented by formula (II), which comprises subjecting a crude salt product formed from said pyridine compound and an acid to an active carbon treatment in a solvent containing water, thereby purifying the pyridine compound.
Other and further features and advantages of the invention will appear more fully from the following description.
The present invention resides in a producing method of a pyridine compound described below.
(1) A method for producing a pyridine compound represented by formula (II), comprising oxidizing a dihydropyridine compound represented by formula (I), (i) in the presence of at least one acid (in the present specification and the claims, this xe2x80x9cacidxe2x80x9d mentioned herein means an acid other than nitrous acid and nitrite), and at least one compound selected from the group consisting of nitrous acid and a nitrite, or (ii) in the presence of at least one base and a hydrogen peroxide solution: 
wherein each of R1 to R5 independently represents a hydrogen atom, or a substituent; L represents an alkyl group, an alkoxy group, an aryl group, or an aryloxy group, each of which may have a substituent: 
wherein each of R1 to R5 has the same meanings as those of formula (I).
(2) The method for producing a pyridine compound according to item (1), wherein the reaction is conducted in the presence of at least one acid and at least one compound selected from the group consisting of nitrous acid and a nitrite.
(3) The method for producing a pyridine compound according to item (2), wherein said acid is a carboxylic acid.
(4) The method for producing a pyridine compound according to items (2) or (3), wherein said nitrite is an alkali metal nitrite or an alkaline earth metal nitrite.
(5) The method for producing a pyridine compound according to any one of items (2) to (4), wherein each of R1, R2, R4, and R5 represents a hydrogen atom, and R3 represents an aryl group in formula (I) and formula (II) respectively.
(6) A method for producing a pyridine compound represented by formula (II) described below, comprising subjecting a crude salt product formed from said pyridine compound and an acid to an active carbon treatment in a solvent containing water, thereby purifying the pyridine compound: 
wherein each of R1 to R5 independently represents a hydrogen atom, or a substituent.
(7) The method for producing a pyridine compound according to item (6), wherein each of R1, R2, R4, and R5 represents a hydrogen atom, and R3 represents an aryl group in formula (II).
(8) The method for producing a pyridine compound according to item (1), wherein the reaction is conducted in the presence of at least one base and a hydrogen peroxide solution.
(9) The method for producing a pyridine compound according to item (8), wherein said base is an inorganic base, or an alkoxide of an alkali metal or alkaline earth metal.
(10) The method for producing a pyridine compound according to the items (8) or (9), wherein each of R1, R2, R4 and R5 in formulae (I) and (II) is a hydrogen atom.
Next, the production method of the present invention will be explained in detail.
The dihydropyridine compound represented by formula (I), which is used in the present invention, and the pyridine compound represented by formula (II), which is produced by the method of the present invention, are explained.
In formulae (I) and (II), each of R1, R2, R3, R4, and R5 independently represents a hydrogen atom, or a substituent. Examples of the substituent include a halogen atom (e.g., fluorine, chlorine, bromine, iodine), an alkyl group (e.g., methyl, ethyl), an aryl group (e.g., phenyl, naphthyl), an alkenyl group (e.g., vinyl), a cyano group, a formyl group, a carboxyl group, an alkoxycarbonyl group (e.g., methoxycarbonyl), an aryloxycarbonyl group (e.g., phenoxycarbonyl), a substituted or unsubstituted carbamoyl group (e.g., carbamoyl, N-phenylcarbamoyl, N,N-dimethylcarbamoyl), an alkyl carbonyl group (e.g., acetyl), an arylcarbonyl group (e.g., benzoyl), a nitro group, a substituted or unsubstituted amino group (e.g., amino, dimethyl amino, anilino), an acylamino group (e.g., acetamido, ethoxycarbonylamino), a sulfonamido group (e.g., methanesulfonamido), an imido group (e.g., succinimido, phthalimido), an imino group (e.g., benzylideneamino), a hydroxyl group, an alkoxy group (e.g., methoxy), an aryloxy group (e.g., phenoxy), an acyloxy group (e.g., acetoxy), an alkylsulfonyloxy group (e.g., methane sulfonyloxy), an arylsulfonyloxy group (e.g., benzenesulfonyloxy), a sulfo group, a substituted or unsubstituted sulfamoyl group (e.g., sulfamoyl, N-phenylsulfamoyl), an alkylthio group (e.g., methylthio), an arylthio group (e.g., phenylthio), an alkylsulfonyl group (e.g., methanesulfonyl), an arylsulfonyl group (e.g., benzenesulfonyl), a silyl group (e.g., dimethylphenylsilyl, triphenylsilyl), a phosphoryl group (e.g., dimethoxyphosphoryl), a heterocyclic group (e.g., 3- to 10-membered saturated or unsaturated heterocyclic group containing at least one of N, O and S atoms, in which sail ring may be a single ring or a condensed ring formed by condensation with another ring; such heterocyclic group is preferably a 5- or 6-membered heterocyclic group, more preferably a 5-membered heterocyclic group containing a nitrogen atom). Besides, the aforementioned substituent may be further substituted with an additional substituent. In case where two or more substituents are involved, they may be the same or different. Further, the substituents which adjoin each other, may combine together to form a ring.
Each of R1, R2, R3, R4, and R5 is preferably a hydrogen atom, a halogen atom, an alkyl group, an aryl group, an alkenyl group, a cyano group, a formyl group, a carboxyl group, an alkoxycarbonyl group, an aryloxycarbonyl group, a substituted or unsubstituted carbamoyl group, an alkylcarbonyl group, an arylcarbonyl group, a nitro group, a substituted or unsubstituted amino group, an acylamino group, a sulfonamido group, a hydroxyl group, an alkoxy group, an aryloxy group, an acyloxy group, a sulfo group, a substituted or unsubstituted sulfamoyl group, an alkylthio group, an arylthio group, an alkylsulfonyl group, an arylsulfonyl group, a silyl group, a phosphoryl group and a heterocyclic group.
Each of R1, R2, R3, R4, and R5 is more preferably a hydrogen atom, a halogen atom, an alkyl group, an aryl group, an alkenyl group, a cyano group, a formyl group, an alkoxycarbonyl group, an aryloxycarbonyl group, a substituted or unsubstituted carbamoyl group, an alkylcarbonyl group, an arylcarbonyl group, a nitro group, an acylamino group, an alkoxy group, an aryloxy group, an acyloxy group, an alkylthio group, an arylsulfonyl group, a silyl group, a phosphoryl group and a heterocyclic group.
For the case of producing a pyridine compound in the presence of a base, a carboxyl group may also be mentioned as a more preferable example of R1 to R5.
Each of R1, R2, R3, R4, and R5 is furthermore preferably a hydrogen atom, a halogen atom, an alkyl group, an aryl group, a cyano group, a formyl group, an alkoxycarbonyl group, an aryloxycarbonyl group, a substituted or unsubstituted carbamoyl group, an alkylcarbonyl group, an arylcarbonyl group, an alkoxy group, an aryloxy group, an acyloxy group, and a heterocyclic group.
For the case of producing a pyridine compound in the presence of a base, a carboxy group may also be mentioned as a furthermore preferable example of R1 to R5.
It is especially preferable that each of R1, R2, R4 and R5 represents a hydrogen atom, and R3 represents an aryl group.
In formula (I), L represents an alkyl group, an alkoxy group, an aryl group, or an aryloxy group, each of which may have a substituent. The alkyl, alkoxy, aryl, or aryloxy group represented by L may be further substituted with a substituent. As the substituent, those substituents exemplified as R1 to R5 may be properly used.
With regard to L, each of the alkyl group and the alkoxy group may be those having preferably 1 to 30 carbon atoms, more preferably 1 to 20 carbon atoms, and furthermore preferably 1 to 15 carbon atoms. They may be branched or may form a ring structure, i.e., they may be a branched alkyl group, a branched alkyloxy group, a cycloalkyl group, or a cycloalkoxy group.
With regard to L, each of the aryl group and the aryloxy group may be those having preferably 6 to 30 carbon atoms, more preferably 6 to 20 carbon atoms, and furthermore preferably 6 to 11 carbon atoms.
Next, specific examples of the compound represented by formula (I) for use in the present invention are shown below. However, the present invention is not limited to these compounds. 
Next, specific examples of the compound represented by formula (II) according to the present invention are shown below. However, the present invention is not limited to these compounds. 
Next, a producing method of the compound represented by formula (II) will be explained in detail.
Various methods for the synthesis of the dihydropyridine compounds represented by formula (I), which are raw materials, are known. For example, they can be advantageously synthesized by an addition reaction of a nucleophilic reagent to a quaternary pyridinium salt (for example, methods as described in J. Org. Chem., 47, 4315-4319 (1982); Heterocycles, 36 (3), 507-518 (1993); ibid. 43 (11), 2425-2434 (1996); ibid. 46, 83-86 (1996); ibid. 48 (12), 2653-2660 (1998); ibid. 51 (4), 737-750 (1999); J. Heterocycl. Chem., 34 (1) 129-142 (1997); Tetrahedron Lett., 40 (22), 4231-4234 (1999); ibid., 40 (22), 4231-4234 (1999); ibid., 40 (34), 6241-6244 (1999); J. Med. Chem., 42 (5), 779-783 (1999); JP-A-10-114743).
The method for producing the compound represented by formula (II) from the aforementioned dihydropyridine compounds represented by formula (I) in the presence of at least one acid, and at least one compound selected from the group consisting of nitrous acid and a nitrite, is explained below in detail.
The acid, which is used in the reaction according to the present invention, may be inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid, or organic acids such as carboxylic acids and sulfonic acids. Two or more of these acids may be used in combination.
The acid is preferably hydrochloric acid, hydrobromic acid, sulfuric acid, and carboxylic acids, and more preferably carboxylic acids. Among carboxylic acids, acetic acid is particularly preferred.
The amount to be added of the acid, which is used in the reaction according to the present invention, is preferably in the range of 1 to 100 times, and more preferably in the range of 1 to 20 times that of the dihydropyridine compound in terms of mole.
In the reaction according to the present invention, at least one compound selected from the group consisting of nitrous acid and a nitrite is used. With respect to the nitrous acid and nitrite, two or more of them may be used in combination. Among nitrous acid and nitrite, an nitrite is preferred.
Similar to the above, two or more of said nitrites may be used in combination. The nitrites are preferably alkali metal nitrites or alkaline earth metal nitrites, more preferably sodium nitrite, potassium nitrite, calcium nitrite, and lithium nitrite, and particularly preferably sodium nitrite and potassium nitrite.
Further, the nitrite may be supplied for the reaction in the solid form, or otherwise may be added in the form of an aqueous solution.
The addition amount of the nitrous acid or nitrite to be used in the reaction according to the present invention, is preferably 1 to 50 times that of the dihydropyridine compound, and more preferably 1 to 15 times that of the dihydropyridine compound, in terms of mole.
The addition order of the raw materials is not particularly limited. However, as a representative procedure, an aqueous solution of a nitrite is added to a solution of a dihydropyridine compound and an acid.
The reaction according to the present invention may be conducted in the absence of a solvent, or otherwise in the presence of a solvent. The solvent to be used in the reaction is not limited, so long as it does not directly participate in the reaction such as substitution reaction and addition reaction, with the compounds represented by formulae (I) and (II). For example, water and organic solvents can be used. Examples of the organic solvents include alcohol (e.g., methanol, ethanol, 2-propanol, n-butanol), ketones (e.g., acetone, methylethyl ketone), esters (e.g., ethyl acetate, methyl acetate, butyl acetate), aliphatic hydrocarbons (e.g., n-pentane, n-hexane, cyclohexane), aromatic hydrocarbons (e.g., toluene, xylene, chlorobenzene), ethers (e.g., diethylether, tetrahydrofuran, dioxane), amides (e.g., N,N-dimethylformamide, N,N-dimethylacetamide, 1-methyl-2-pyrolidone), dimethysulfoxide, sulfolane, acetonitrile, and acetic acid.
Among these solvents, preferred are water, methanol, ethanol, 2-propanol, acetone, methylethyl ketone, ethyl acetate, n-hexane, cyclohexane, toluene, xylene, tetrahydrofuran, N,N-dimethylacetamide, acetonitrile, and acetic acid, more preferably water, methanol, 2-propanol, acetone, ethyl acetate, toluene, acetonitrile, and acetic acid. Further, two or more of these solvents may be used in combination.
Generally, a reaction temperature of the reaction according to the present invention is preferably in the range of xe2x88x9210xc2x0 C. to 120xc2x0 C., more preferably in the range of 0xc2x0 C. to 60xc2x0 C. Besides, a reaction time differs depending on conditions such as a reaction raw material, a reaction temperature, a reaction concentration, and a reaction scale, but ordinarily in the range of 0.1 to 36 hours, and preferably in the range of 0.5 to 12 hours.
The method for the purification of the pyridine compound according to the present invention is explained below in detail.
After completion of the reaction in the production of the pyridine compound, a crude product of the pyridine compound can be obtained by means of an ordinary method such as crystallization caused by addition to a poor solvent, and a course of operations consisting of extraction, washing, and concentration.
As a method suitable for isolating and purifying a pyridine compound with a high purity from such the crude product, the present inventors have newly found a method in which a crude salt product formed from the pyridine compound and an acid is subjected to an active carbon treatment in a solvent containing water.
Further, the purification method according to the present invention can be applied not only to the pyridine compound obtained by the aforementioned producing method of the present invention, but also to any other pyridine compounds.
The acid to form the crude salt product with the pyridine compound, which salt is used in the purification method according to the present invention, may be inorganic acids such as, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid, or otherwise organic acids such as, carboxylic acids, and sulfonic acids. Further, two or more of these acids may be used in combination.
Among these acids, preferred are hydrochloric acid, hydrobromic acid, sulfuric acid, carboxylic acids, and sulfonic acids, more preferably sulfuric acid, carboxylic acids, and sulfonic acids, furthermore preferably sulfuric acid, oxalic acid, succinic acid, methane sulfonic acid, benzene sulfonic acid, and p-toluene sulfonic acid, and particularly preferably sulfuric acid, methane sulfonic acid, and p-toluene sulfonic acid.
An amount of the acid used in the purification method according to the present invention is generally in the range of 0.5 to 50 times, preferably in the range of 0.5 to 20 times, that of the pyridine compound in terms of mole. The crude salt product formed from the pyridine compound and the acid may be subjected to an active carbon treatment once isolated in the solid form. Alternatively, the salt may be subjected to an active carbon treatment omitting such isolation operation.
In the purification method according to the present invention, other solvents may be used in addition to water. As the solvents, preferred are water-soluble solvents, more preferred are methanol, ethanol, 2-propanol, acetone, tetrahydrofuran, and actonitrile, and furthermore preferred are methanol, ethanol, and 2-propanol. Further, two or more of these solvents may be used in combination.
A content of water in these solvents is preferably in the range of 50 to 100%, more preferably in the range of 70 to 100%, and most preferably 100%, that is only water is used as the solvent.
The amount of the solvent containing water, which is used in the purification method according to the present invention, is generally in the range of 0.5 to 100 times, and preferably in the range of 1 to 50 times, that of the pyridine compound in terms of weight part.
The active carbon, which is used in the purification method according to the present invention, is not limited in particular, and articles on the market can be used. The amount of the active carbon used is generally in the range of 0.01 to 10 times, and preferably in the range of 0.01 to 1 time, that of the pyridine compound in terms of weight part.
The temperature of the active carbon treatment in the purification method according to the present invention is generally in the range of 0xc2x0 C. to 150xc2x0 C., and preferably in the range of 20xc2x0 C. to 120xc2x0 C. The time of the active carbon treatment is generally in the range of 10 minutes to 12 hours, and preferably in the range of 10 minutes to 6 hours. After the active carbon treatment, active carbons are removed by filtration and then, the filtrate is neutralized with a base to isolate a pyridine compound. The base for use in the neutralization may be a hydroxide, carbonate, hydrogen carbonate, phosphate, carboxylate, and alkoxide of an alkali metal or alkaline earth metal. In addition, organic bases such as amines (e.g., ammonia, diethylamine, triethylamine) may be used. Further, two or more of these bases may be used in combination. Among these bases, preferred are a hydroxide, carbonate, and hydrogen carbonate of an alkali metal, and sodium methoxide, ammonia, and more preferred are sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium methoxide, and ammonia.
Next, the method for the producing the pyridine compound represented by formula (II) from the dihydropyridine compound represented by formula (I) in the presence of at least one base, and a hydrogen peroxide solution, is explained in detail.
The base, which is used in the reaction according to the present invention, is not limited in particular, and for example, a hydroxide, carbonate, hydrogen carbonate, phosphate, carboxylate, and alkoxide of an alkali metal or alkaline earth metal may be used. In addition, organic bases such as amines (e.g., ammonia, diethylamine, triethylamine) may also be used. Two or more of these bases may be used in combination.
Among these bases, preferred are a hydroxide, carbonate and hydrogen carbonate of an alkali metal, sodium methoxide, and ammonia, more preferred are sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, lithium carbonate, sodium methoxide, sodium ethoxide, and ammonia, and particularly preferred are sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, lithium carbonate, and sodium methoxide.
The amount to be added of the base, which is used in the reaction according to the present invention, is preferably in the range of 1 to 100 times, and more preferably in the range of 1 to 20 times, that of the dihydropyridine compound in terms of mole.
The concentration of a hydrogen peroxide solution, which is used in the reaction according to the present invention, is not limited in particular. Therefore, articles on the market may be used, or otherwise a diluted one may be used. The concentration of the hydrogen peroxide solution used is generally in the range of 1 to 80% by weight, preferably in the range of 3 to 70% by weight, and particularly preferably in the range of 5 to 50% by weight.
The amount to be added of the hydrogen peroxide solution, which is used in the reaction according to the present invention, is an appropriate amount that provides hydrogen peroxide preferably in the range of 1 to 100 times, more preferably in the range of 1 to 20 times, that of the dihydropyridine compound, in terms of mole.
The addition order of the raw materials is not limited in particular. Therefore, a dihydropyridine compound, a solvent, a base, and a hydrogen peroxide solution may be added at the same time. Alternatively, for example, after heating a dihydropyridine compound and a solvent in the presence of a base, a hydrogen peroxide solution may be added.
As in the case for producing the pyridine compound in the presence of an acid, the reaction may be conducted in the presence of a solvent in the case for producing the pyridine compound in the presence of a base. The examples of the organic solvents in the reaction in the presence of a base are those mentioned for the reaction in the presence of an acid, except for an acetic acid is excluded.
Further, among those solvents, preferred are water, methanol, ethanol, 2-propanol, acetone, methylethyl ketone, ethyl acetate, n-hexane, cyclohexane, toluene, xylene, tetrahydrofuran, and acetonitrile, more preferred are water, methanol, ethanol, 2-propanol, acetone, ethyl acetate, toluene, and acetonitrile, and particularly preferred are water, methanol, ethanol, and 2-propanol. Further, two or more of these solvents may be used in combination.
Generally, a reaction temperature of the reaction according to the present invention is preferably in the range of xe2x88x9210xc2x0 C. to 120xc2x0 C., and more preferably in the range of 10xc2x0 C. to 100xc2x0 C. Besides, a reaction time differs depending on conditions such as a reaction raw material, a reaction temperature, a reaction concentration and a reaction scale, but ordinarily the time is in the range of 0.1 to 36 hours, and preferably in the range of 0.5 to 12 hours.
According to the present invention, it becomes possible to produce a pyridine compound, which is useful for photographic additives, sensitizing dyes, pharmaceuticals, organic EL materials, liquid crystal materials, nonlinear optical materials, and so on, or synthetic intermediates of these materials, by an industrially advantageous method with low cost, high yield and excellent production suitability. Also, it becomes possible to produce such a pyridine compound with a method, which is industrially advantageous and environment-oriented. Further, according to the present invention, it is possible to manufacture a pyridine compound with a high purity, by means of a specific active carbon treatment.
Next, the present invention will be explained in more detail based on examples, but the present invention is not meant to be limited by those examples.